While the prevalence of multi-drug resistant pathogens continues to rise, the rate at which new clinical antimicrobials are introduced has declined significantly. In addition, the treatment of persistent infections has been complicated by pathogen phenotypes. Bacteria that grow very slowly are often associated with prolonged infections, and they are particularly tolerant to many of the clinically important classes of antibiotics that inhibit rapidly growing cells. For example, the β-lactam family of antibiotics inhibits enzymes involved in the synthesis of peptidoglycan, and is thus most effective at targeting microbes that grow rapidly and continuously synthesize new cell wall. Relying on antibiotics that require fast metabolism and growth creates long-term problems, as dormant bacteria, as well as those associated with biofilms and other multicellular structures, may survive antibiotic treatments, become predisposed to developing drug resistance, and cause a relapse.
An effective strategy for combating slow-growing bacteria is to target the lipid membrane. Proteomic analyses have demonstrated that approximately one third of all proteins in bacteria are associated with membranes. Peripheral and integral membrane proteins participate in various essential cellular processes, including: nutrient and waste transport, respiration, adhesion, mobility, cell-cell communication, and the transfer of genetic material. Compounds that perturb these processes disrupt growth and the maintenance of cell homeostasis and may serve as potent therapeutic antimicrobial agents.
Synthetic and naturally occurring small molecules that disrupt the bacterial membrane have been developed to treat persistent infections of Mycobacterial and Staphylococcal species. This class of compounds exhibits multiple mechanisms of action, including: the inhibition of specific enzymatic processes in the membrane, decreasing the trans-membrane potential (ΔΨ), and increasing membrane permeability. The increase in permeability may act as a double-edged sword, as it perturbs bacterial physiology and facilitates the penetration of free radicals secreted by macrophages of the host immune system.
The therapeutic benefit of membrane-active drugs has been demonstrated against dormant bacteria; however, there are no clear design rules for small molecules that are specific for bacterial versus eukaryotic membranes. Many of the members of this class of antibiotics are ineffective against Gram-negative bacteria, presumably due to the outer membrane. The identification of new broad-spectrum antibiotics that target bacterial membranes and the study of their mechanism of toxicity would provide an important step forward for this field.
What are needed are new broad-spectrum antimicrobial compounds, particularly antimicrobial compounds that target bacterial membranes.